Doxorubicin (DOX) is one of the most potent antineoplastic agents used in the treatment of lymphoid malignancies and solid tumors in both adults and children. However, its clinical use is limited by a cumulative myocardial toxicity that can eventually lead to heart failure. Specifically, the broad, long-term objective of this project is to determine the effects of exercise on the chronic cardiac dysfunction associated with DOX treatment and investigate mechanisms that may be involved with any exercise-induced cardioprotection. Three specific aims will provide the framework for this proposal: Specific Aim 1) Determine if exercise training before, during, and after DOX treatment, can attenuate DOX-induced chronic cardiac dysfunction. It has not yet been determined if the beneficial effects of exercise are maintained weeks, or even months, following treatment in animal models. This specific aim will be addressed by allowing rats to voluntarily exercise for 10 weeks, after which they will be treated with DOX (1 mg/kg/day for 10 days) and observed for up to 16 weeks after DOX treatment. During this observation period cardiac function will be periodically assessed using echocardiography and the isolated perfused heart. It is hypothesized that exercise prior to DOX treatment will attenuate DOX cardiotoxicity for up to 16 weeks following DOX treatment. Specific Aim 2) Determine if exercise training during and after DOX treatment can alleviate the chronic cardiac dysfunction that accompanies DOX treatment. Here, a series of experiments is proposed to investigate the effects of exercise training on DOX cardiotoxicity when exercise is initiated at the time DOX treatment begins. In these studies, rats will be allowed to voluntarily exercise beginning the same day a 10-day DOX regimen begins (1 mg/kg/day for 10 days). Cardiac function will be assessed by echocardiography and the isolated perfused heart before and after DOX treatment. It is hypothesized that exercise will be cardioprotective, even when initiated after DOX treatment begins. Specific Aim 3) Investigate the role oxidative stress and apoptosis may play in mediating the beneficial effects, or lack thereof, of exercise on chronic DOX cardiotoxicity. While several mechanisms may be involved, oxidative stress and apoptosis appear to be two means by which DOX cardiotoxicity is mediated. Specific Aim 3 will address the role these processes may play in the cardioprotective effects of exercise. At specified times before and after DOX treatment, hearts will be obtained and analyzed for several markers of oxidative stress and apoptosis. It is hypothesized that exercise training will attenuate the oxidative and apoptotic events associated with DOX. Although improvements in cancer treatment strategies have been witnessed in recent decades, doxorubicin cardiotoxicity remains a clinical dilemma. In order to reap optimal benefits from this drug, it has become necessary to develop complementary therapies that offset DOX cardiotoxicity. We believe that exercise training is a strategy that may provide significant cardiovascular benefits for cancer patients undergoing treatment with doxorubicin. Exercise training in patients undergoing doxorubicin treatment may be able to better tolerate exposure to doxorubicin, or possibly tolerate higher doses of doxorubicin. Such an improved response to doxorubicin treatment may ultimately increase cure rate, long-term survival, and the quality of life for cancer survivors. [unreadable] [unreadable] [unreadable]